Project Summary/Abstract Parkinsonian syndromes (PS) are common and progressive neurodegenerative disorders that encompass a spectrum of movement disabilities. Despite their distinctive pathological signatures and patterns of brain changes, PS cause overlapping motor signs including bradykinesia, rigidity, and/or tremor, probably due to shared dysfunction of basal ganglia (BG)- and cerebellar-related structures. The current diagnosis and staging of PS as well as other neurodegenerative diseases are based on the pattern of neuronal cell loss or death, gliosis, and molecular markers. Among PS, the most common form is Parkinson's disease (PD), defined pathologically by neuronal loss in the substantia nigra (SN) of the BG and presence of ?-synuclein (?Syn) positive Lewy body (LB) aggregation, although many other regions also are involved. Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are also common PS, and are known for neuronal loss in different brain regions including the BG, pons, cerebellum, and related structures. PSP characteristically has tau-positive inclusions in both glia and neurons, whereas MSA typically has glial cytoplasmic inclusions that are ?-Syn positive. Currently, no in vivo biomarkers are approved to differentiate these clinically similar syndromes, capture the distinctive pathological pattern and molecular characteristics, and/or track the progression of each PS. The literature and our preliminary data lead to our premise that combining state-of-the-art multimodal MRI (Aim 1) with biofluid markers of misfolded ?Syn and tau (Aim 2) will yield objective and quantitative biomarker(s) that provide complimentary information about PS, differentiate PS from each other, quantify disease progression, and provide insights into the unique neuropathology associated with each PS. Since 2012, the Penn State team led by Dr. Huang, supported by the NINDS PD Biomarker Program, has recruited and studied a cohort totaling 270 PS patients (120 PD, 27 PSP, 30 MSA) and 93 Controls. Data collected to date include longitudinal multimodal MRI (T1, T2, diffusion & susceptibility), clinical data (NIH common data elements-CDE), and biofluids (plasma, serum, & CSF). We also have 24 postmortem brains from this cohort. The proposed study will be especially cost-efficient by leveraging this existing cohort, data, and its banked biofluids, and will expand the sample size of PSP and MSA patients. This will yield a total dataset of ?60 subjects in each PS and control group for cross-sectional analyses, ?40 in each PS and control group for longitudinal analyses, and ?60 postmortem brains by 2023. In collaboration with the team led by multi-PI Dr. Kanthasamy (Iowa State), Aim 1 will determine the distinct patterns of MRI in PS and their clinical/pathological substrates. Aim 2 will test exosomal misfolded ?Syn and tau as biomarkers for PS & their progressions. Aim 3 will combine multimodal MRI & misfolded ?Syn/tau to discriminate PS/delineate progression. The successful completion of these Aims may reveal biomarkers that would be of importance in the clinical and differential diagnosis of PS, and in assessing potential disease-modifying therapies.